Peptidase is known to relate to various diseases. Dipeptidyl dipeptidase IV (hereinafter sometimes to be abbreviated as DPP-IV), which is one kind of peptidases, is serine protease that specifically binds with a peptide containing proline (or alanine) at the 2nd from the N terminal and cleaves the C-terminal side of the proline (or alanine) to produce dipeptide. DPP-IV has been shown to be the same molecule as CD26, and reported to be also involved in the immune system. While the role of DPP-IV in mammals has not been entirely clarified, it is considered to play an important role in the metabolism of neuropeptides, activation of T cells, adhesion of cancerous cells to endothelial cells, invasion of HIV into cells and the like. Particularly, from the aspect of glycometabolism, DPP-IV is involved in the inactivation of GLP-1 (glucagon-like peptide-1) and GIP (Gastric inhibitory peptide/Glucose-dependent insulinotropic peptide), which are incretins. With regard to GLP-1, moreover, its half-life in plasma is as short as 1-2 minutes, and GLP-1 is known to be degraded by DPP-IV and markedly lose its physiological activity because GLP-1(9-36)amide, which is a degradation product by DPP-IV, acts on GLP-1 receptor as an antagonist. It is also known that suppression of degradation of GLP-1 by inhibiting activity of DPP-IV leads to potentiation of physiological activity that GLP-1 shows, such as glucose concentration-dependent insulinotropic effect and the like. From these facts, a compound having a DPP-IV inhibitory activity is expected to show effect on impaired glucose tolerance, postprandial hyperglycemia and fasting hyperglycemia observed in type I and type II diabetes and the like, obesity or diabetic complications associated therewith and the like.
As therapeutic agents of diabetes now in use, a sulfonylurea, a biguanide, an α-glucosidase inhibitor and the like are known. While a sulfonylurea produce a potent hypoglycemic action, it sometimes causes serious hypoglycemia and requires attention during use. A biguanide easily causes lactic acidosis which is a relatively serious side effect. An α-glucosidase inhibitor delays digestion and absorption of glucose in the gastrointestinal tract and suppresses increase in the blood glucose level after meal, but side effects of sense of distension, diarrhea and the like are problematic (see JOSLIN'S DIABETES MELLITUS, 13th Edition, pp. 521-522).
As a fused heterocyclic compound having an amino group, the following compounds have been reported.
(1) A compound having a melanin-concentrating hormone antagonistic action, which is represented by the formula
wherein Ar1 is a cyclic group optionally having substituents;X and Y are the same or different and each is a spacer having 1 to 6 atoms in the main chain;Ar is a fused polycyclic aromatic ring optionally having substituents;R1 and R2 are the same or different and each is hydrogen atom or hydrocarbon group optionally having substituents, or R1 and R2 may form, together with the adjacent nitrogen atom, a nitrogen-containing heterocycle optionally having substituents, R2 may form, together with the adjacent nitrogen atom and Y, a nitrogen-containing heterocycle optionally having substituents, and R2 may form, together with the adjacent nitrogen atom, Y and Ar, a fused ring or a salt thereof (see WO01/82925).(2) a compound having a DPP-IV inhibitory action, which is represented by the formula
(see Bioorganic & Medicinal Chemistry Letters, vol. 10, pp. 1555-1558 (2000)).
However, there is no report about the compound of the present invention.
There is a demand on the development of a fused heterocyclic compound having a peptidase inhibitory activity, useful as a prophylactic or therapeutic agent of diabetes and the like and having superior properties in terms of efficacy, duration of action, specificity, low toxicity and the like.